Innate defenses against enterotoxigenic E. coli as potential therapeutic contributors

针对产肠毒素大肠杆菌的先天防御作为潜在的治疗贡献者

• 批准号: 10745567
• 负责人: Jennifer Foulke-Abel
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745567
• 关键词: Acute; Adhesions; Animals; Apical; Attention; Bacteria; Cancer cell line; Cells; Clinical; Clinical Research; Coculture Techniques; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Diarrhea; Disease; Disease Outbreaks; Drug Design; Enabling Factors; Enteral; Enterotoxins; Environment; Epithelium; Escherichia coli; Escherichia coli Infections; Functional disorder; Goals; Host Defense; Human; IL8 gene; Image; Immune; Immune response; Immunization; Immunology; Infection; Inflammation; Inflammatory; Innate Immune Response; Intention; Interleukin-1 beta; Intervention; Intestines; Investigation; Knowledge; Macrophage; Methodology; Modeling; Molecular; Multicenter Studies; Oxygen; Pathogenesis; Pathogenicity; Peptides; Phase; Phenotype; Physiological; Population; Production; Protein Subunits; Reaction; Regulation; Research; Role; Second Messenger Systems; Shigella; Shigella Infections; Signal Induction; Signal Transduction; Small Intestines; Therapeutic; Tissues; Transcript; Vaccine Design; Vaccines; Variant; Work; adaptive immunity; antimicrobial peptide; beta-Defensins; burden of illness; cell type; cytokine; design; diarrheal disease; enteroaggregative Escherichia coli; enterotoxigenic Escherichia coli; extracellular; follow-up; gut bacteria; human model; immune activation; improved; innovation; insight; intestinal epithelium; intraepithelial; microbiome; model development; monocyte; monolayer; neutrophil; novel; pathogen; pathogenic bacteria; peripheral blood; pre-clinical; response; scaffold; synergism; targeted treatment; therapeutic target; therapy development; tool; vaccine strategy; γδ T cells

PROJECT SUMMARY The bacterial pathogen enterotoxigenic E. coli (ETEC) contributes to the global burden of diarrheal disease because vaccine protection and therapy remain inadequate. A long-term goal is to improve knowledge of innate immune responses to ETEC infection, as they are likely important for initiating durable adaptive immunity. The objective of this project is to understand the innate immune defenses employed by human intestine to sense and eliminate ETEC, thus informing strategies for vaccine and/or drug design. We will (Aim 1) characterize the recognition and response mechanisms employed by tissue resident macrophages and neutrophils against ETEC infection. In a complementary inquiry, we will (Aim 2) assess antimicrobial peptides (AMPs) released by epithelial and immune cells in response to ETEC that could serve as potential treatment. These aims will be explored in primary co-culture models of human small intestinal epithelium (tissue-derived enteroids) and immune cell types from peripheral blood that are assembled on scaffolds to facilitate physiologically relevant crosstalk between bacteria, epithelia, and immune cell populations. Model development, application of anaerobic environment to mimic conditions in the intestinal lumen, and characterization will combine the expertise of the Enteroid and Immunology Cores that support this P01. The proposed studies are significant in that they will indicate the molecular signal transduction involved in reacting to and resolving ETEC infection without clinically overt inflammation, an understudied aspect of acute pathogenic diarrheal disease. Results from these studies will be compared to findings from enteroaggregative E. coli and Shigella pathogenesis proposals in this P01 to identify common effectors for therapeutic targeting. The projects of this P01 will cumulatively innovate human primary epithelial and immune cell co-culture strategies for host-pathogen research.

项目摘要 致病性肠球菌E.大肠杆菌（ETEC）导致全球疟疾负担 因为疫苗保护和治疗仍然不足。一个长期目标是提高对 对ETEC感染的先天免疫应答，因为它们可能对启动持久的适应性免疫应答非常重要。 免疫力本项目的目的是了解人类先天性免疫防御系统， 肠检测和消除ETEC，从而为疫苗和/或药物设计提供信息。目标（Aim） 1)表征组织驻留巨噬细胞所采用的识别和应答机制， 中性粒细胞对ETEC感染的抵抗。在补充调查中，我们将（目标2）评估抗菌肽 （AMP）由上皮细胞和免疫细胞响应ETEC释放，可作为潜在的治疗。 这些目的将在人小肠上皮（组织来源的上皮细胞）的原代共培养模型中进行探索。 肠类）和来自外周血的免疫细胞类型，其组装在支架上以促进 细菌、上皮细胞和免疫细胞群体之间的生理学相关串扰。模型 开发、应用厌氧环境模拟肠腔条件，以及 表征将结合支持此P01的肠上皮细胞和免疫学核心的专业知识联合收割机。的 提出的研究是重要的，因为它们将表明参与反应的分子信号转导。 治疗和解决ETEC感染而无临床明显炎症，这是急性ETEC感染的一个未充分研究的方面。 病原性腹泻病这些研究的结果将与肠聚集性 E.大肠杆菌和志贺氏菌致病机制的建议，以确定共同的效应治疗靶向。 本P01项目将累积创新人类原代上皮细胞和免疫细胞共培养 宿主-病原体研究的策略。